Stannous oral compositions

ABSTRACT

The present invention relates to oral compositions comprising a stannous ion source, a fluoride ion source, and a polymeric mineral surface active agent that binds stannous, said compositions providing adequate therapeutic efficacy with minimal side effects of tooth staining and astringency. The composition simultaneously provides reduction and control of supragingival calculus. The present oral care compositions may be formulated as single phase or dual phase compositions. The present invention also provides a method for effective delivery of stannous-containing compositions with minimal side effects of tooth staining or astringency and with effective tartar control by administering to a subject a stable dentifrice composition comprising a clinically effective amount of stannous fluoride and/or other stannous salts in combination with a fluoride ion source and a polymeric mineral surface active agent, preferably a phosphate- or phosphonate-containing polymer.

This application is a divisional of U.S. application Ser. No.09/710,440, filed Nov. 10, 2000, now U.S. Pat. No. 6,555,094, and whichclaims the benefit of U.S. Provisional Application No. 60/165,350, filedNov. 12, 1999.

TECHNICAL FIELD

The present invention relates to improved oral compositions containingstannous salts, such as stannous fluoride. These improved compositionsprovide a spectrum of intraoral benefits derived from stannous fluorideand/or other stannous salt, including antimicrobial effects, control ofbreath malodor, control of dental plaque growth and metabolism, reducedgingivitis, decreased progression to periodontal disease, reductions indentinal hypersensitivity and reduced coronal and root dental caries.These improved compositions provide the aforementioned benefits withsignificant improvements compared to conventional stannous containingcompositions, including: 1) reduced levels of dental staining; 2)reduced astringency thereby improving aesthetic characteristics of thecompositions; and 3) reduction in dental calculus formation. Theimproved stannous containing compositions provide these benefitsprimarily through the combined effects of stannous and polymeric mineralsurface active agents, preferably including anionic polymers, such ascondensed polyphosphate or polyposphonate. The invention also relates tomethods of at least maintaining therapeutic efficacy while decreasingstaining and improving the aesthetic desirability of oral compositionscontaining stannous salts, such as stannous fluoride.

BACKGROUND OF THE INVENTION

Stannous fluoride is commonly known for its efficacy when formulatedinto oral products. Stannous fluoride was the first fluoride sourceincorporated into toothpastes for therapeutic efficacy in the control ofdental caries. Stannous fluoride gels, rinses, and dentifrices havesince been shown to provide clinical efficacy for the reduction ofdental caries, dentinal hypersensitivity, dental plaque and gingivitis.In addition to these clinical effects, formulations containing stannousfluoride may also help to provide improved breath benefits throughchemical and antibacterial actions. Stannous fluoride formulationstypically include stabilization systems designed to maintainbioavailable (i.e., soluble and reactive) levels of stannous duringshelf storage, accounting for loss of stannous to oxidation orprecipitation. Therefore, stannous fluoride formulations may containother additional stannous containing ingredients, which may provideimportant stabilization benefits for efficacy. High concentrations ofstannous in dental formulations help to ensure stability of stannousfluoride and therefore clinical efficacy of formulations containing thelatter. Unfortunately, although stannous fluoride compositions are knownto be highly effective, successful commercial utilization is complicatedby complexity in the development of formulations providing adequatestannous fluoride stability and in the side effects of stannous.Formulations providing increased or improved efficacy typically promoteincreased side effects. This limits clinical and commercialapplications.

One of the most notable side effects of regular use of stannous fluorideis yellow-brown tooth staining. This stain is derived from pellicle,plaque and dietary component reactions with available stannous depositedon tooth surfaces during treatment with effective stannous fluorideformulations.

A second side effect routinely encountered during use of effectivestannous fluoride formulations is unacceptable formulation astringency.Astringents are locally applied protein precipitants whose low cellpermeability restricts actions to cell surfaces and interstitial spaces.Strong astringents can induce contraction and wrinkling of the tissuesand mucous secretions can be precipitated or reduced. Within oralproducts, these chemical actions produce an unpleasant ‘drying’sensation in the oral cavity, such as on the tongue, gingival tissues orbuccal epithelia. Stannous formulations containing sufficient stannousfor bioavailability are routinely described as astringent by patientsand consumers and this property is undesirable. The astringency is mostnoticeable after use of the product.

A third side effect of the regular use of stannous fluoride dentifricecompositions is the decreased efficacy in reducing dental calculus withthese compositions. The present inventors have established that stannousfluoride dentifrices proven effective for antimicrobial, antigingivitisand other expected benefits do not always show reproducible clinicalactions toward the prevention of accumulation of undesirablesupragingival dental calculus. The control of supragingival calculusformation along with other clinical benefits is desired byprofessionals, patients and consumers. The multifunctional activity oforal compositions can simplify hygiene and provide a holistic approachto maintenance therapeutic oral health.

Previous attempts to develop effective and consumer acceptable stannousfluoride oral compositions have attempted to solve these cumulativedetriments, however none have been fully successful. U.S. Pat. No.5,004,597, issued to Majeti et al., discloses oral compositionscontaining stannous fluoride and gluconate salts. The inclusion ofstannous gluconate results in improved formulation efficacy andstability. While effective, this formulation produces undesirable levelsof tooth staining. Moreover, the formulation had unacceptableaesthetics, derived primarily from the astringency of stannous.Likewise, U.S. Pat. No. 5,578,293, issued to Prencipe et al., disclosesthe use of an organic acid compound to stabilize the stannous ionconcentration. Coupled with the stannous fluoride and citrate as theorganic acid, the formulations also include soluble pyrophosphate salts.U.S. Pat. No. 4,323,551 to Parran et al., discloses the use ofpyrophosphate salts to provide anticalculus benefits. Clinical researchhas established the potential of anionic mineral surface activeinhibitors, such as pyrophosphates, in preventing the development ofnatural and antimicrobial induced tooth staining. (Grossman, Bollmer,Sturzenberger and Vick; Journal of Clinical Dentistry 6(4): 185-187,1995). In the Prencipe et al. patent, all examples include sufficientamount of either citric acid and/or sodium citrate dihydrate tostabilize the stannous ions and to prevent precipitation. These levelsalso directly inhibit stannous binding to pyrophosphate salts. Ifstannous did bind to the pyrophosphate salts, studies support that thiswould decrease the antimicrobial activity of the stannous fluoride. Thelevel of citrate needed to effectively stabilize the stannous ionagainst precipitation and pyrophosphate binding also significantlydetracts from the aesthetics of the stannous composition. Thecomposition will be salty, sour, and the stannous bound to citrate willstill act as an astringent, which reduces the overall tasteacceptability. U.S. Pat. No. 5,213,790, issued to Lukacovic et al., alsodiscloses the use of a citrate ion source in a stannous composition.U.S. Pat. No. 5,780,015, issued to Fisher et al., discloses the use ofdual phase dentifrice containing a potassium salt and a stannous saltwherein hydrogenated castor oil is used to help reduce astringency. Thestannous salt is stabilized through the use of an organic acid compoundas described in Prencipe et al. Another attempt to produce efficaciousstannous composition is described in U.S. Pat. No. 5,716,600, issued toZhrandik et al. This patent discloses low water formulations which helpto prevent the stannous fluoride from degradation over time. No attemptsare made to reduce the staining of the formulation.

U.S. Pat. No. 5,017,363, issued to Suhonen, discloses a stannous ionchelating copolymer of an alkyl vinyl ether and maleic anhydride or acidin an amount to effectively stabilize stannous ions. Suhonen alsodiscloses that the compositions are substantially free from silica,soluble phosphates such as soluble pyrophosphates (e.g., tetrasodiumpyrophosphate and tetrapotassium pyrophosphate), and aldehyde groupcontaining compounds, since the stabilizing function of the stannous ionchelating polymer is not effective in the presence of these ingredients.

U.S. Pat. No. 5,338,537, issued to White, Jr. et al., discloses the useof a low molecular weight diphosphonic acid, which is used as a bindingagent for stannous to help reduce the tendency of staining from thecomposition. While effective in reducing staining potential, laboratorystudies have demonstrated that the antibacterial activity offormulations containing stannous complexed with the low molecular weightdiphosphonic acid is very low. Similar results are obtained onformulation with soluble pyrophosphate salts, in the absence of strongcitrate chelation, as described above.

Based on the foregoing, it appears that the same chemical andbiochemical binding sites may be involved for bothantibacterial/antiplaque activity and for stabilization and reducing thetooth staining potential of stannous fluoride. Thus, to achievestabilization and/or reduction of tooth staining,antibacterial/antiplaque activity may be compromised. This makes thedevelopment of optimal stannous fluoride oral compositions difficult andexplains the limited number of stannous fluoride compositions in themarketplace today. To improve consumer acceptance and compliance withthe use of oral compositions containing stannous, a stannous compositionis needed which has high efficacy but with low level of staining andother negative aesthetics, such as astringency. Moreover, it isdesirable that these formulations provide simultaneous efficacy towardthe reduction and control of dental calculus formation.

SUMMARY OF THE INVENTION

The present invention relates to oral compositions comprising a stannousion source, a fluoride ion source, and a polymeric mineral surfaceactive agent that binds stannous, said compositions providing adequatetherapeutic efficacy with minimal side effects of tooth staining andastringency. The compositions simultaneously provide reduction andcontrol of supragingival calculus. The present oral care compositionsmay be formulated as single phase or dual phase compositions. Thepresent invention also provides a method for effective delivery ofstannous-containing compositions with minimal side effects of toothstaining or astringency and with effective tartar control byadministering to a subject a stable dentifrice composition comprising aclinically effective amount of stannous fluoride and/or other stannoussalts in combination with a polymeric mineral surface active agent,preferably a phosphate- or phosphonate-containing polymer.

These and other features, aspects, and advantages of the presentinvention will become evident to those skilled in the art from thedetailed description which follows.

DETAILED DESCRIPTION OF THE INVENTION

While the specification concludes with claims, which particularly pointout and distinctly claim the invention, it is believed the presentinvention will be better understood from the following description.

All percentages used herein are by weight of the dentifrice composition,unless otherwise specified. The ratios used herein are molar ratios ofthe overall composition, unless otherwise specified. All measurementsare made at 25° C., unless otherwise specified.

Herein, “comprising” means that other steps and other ingredients whichdo not affect the end result can be added. This term encompasses theterms “consisting of” and “consisting essentially of”.

The oral composition of the present invention may be in the form of atoothpaste, dentifrice, tooth powder, topical oral gel, mouthrinse,denture product, mouthspray, lozenge, oral tablet, or chewing gum.

The term “dentifrice”, as used herein, means paste, gel, or liquidformulations unless otherwise specified. The dentifrice composition maybe in any desired form, such as deep striped, surface striped,multi-layered, having the gel surrounding the paste, or any combinationthereof.

If a dual phase oral composition is desired, each oral composition willbe contained in a physically separated compartment of a dispenser anddispensed side-by-side. The term “dispenser”, as used herein, means anypump, tube, or container suitable for dispensing toothpaste.

The oral composition may be a single phase oral composition or may be acombination of the two or more oral compositions. The oral compositionis a product, which in the ordinary course of administration, is notintentionally swallowed for purposes of systemic administration ofparticular therapeutic agents, but is rather retained in the oral cavityfor a time sufficient to contact substantially all of the tooth surfacesand/or oral tissues for purposes of oral activity. The term “totalcomposition” as used herein means the total composition delivered to theoral cavity, regardless of whether it contains a single phase ormultiple phases.

The term “aqueous carrier” as used herein means any safe and effectivematerials for use in the compositions of the present invention. Suchmaterials include tartar control agents, antibacterial agents, abrasivepolishing materials, peroxide sources, alkali metal bicarbonate salts,thickening materials, humectants, water, buffering agents, surfactants,titanium dioxide, flavor system, sweetening agents, coloring agents, andmixtures thereof.

Herein, the terms “tartar” and “calculus” are used interchangeably andrefer to mineralized dental plaque biofilms.

The term “stannous” as used herein, is defined to mean the stannous thatis in a dentifrice or other oral product, and supplied by a source suchas stannous salts including stannous fluoride. It may refer to thestannous ions that are provided by a stannous salt other than stannousfluoride, added for stabilization purposes.

The present invention relates to oral compositions comprising a stannousion source, a fluoride ion source, and a polymeric mineral surfaceactive agent that binds stannous, said compositions providing adequatetherapeutic efficacy with minimal side effects of tooth staining andastringency. The compositions simultaneously provide reduction andcontrol of supragingival calculus. Aesthetic and astringency benefits ofthe combination of stannous and polymeric mineral surface active agentsare enhanced by concurrent appropriate formulation, includingutilization of suitable poloxamer ingredients.

The polymeric mineral surface active agent is preferably a polyphosphatehaving an average chain length of about 4 or more, a polyphosphonate, orother phosphate- or phosphonate-containing anionic polymers. One havingordinary skill in the art would assume that a polymeric binding agent,such as a polyphosphate having an average chain length of about 4 ormore, would behave similarly to the pyrophosphate or tripolyphosphate instannous containing dentifrice systems. The present inventors have foundthat chemical binding of stannous using pyrophosphate, diphosphonate, ortripolyphosphate to prevent stain formation, also produces unacceptablelosses in therapeutic potential. However, an unexpected result occurswith the present polyphosphate and other phosphate- orphosphonate-containing polymers as they are capable of reducing the sideeffects of dental staining and formulation astringency withoutsignificantly reducing the efficacy of the stannous. The presentinventors have in fact found that including these polymeric mineralsurface active agents in oral compositions containing stannous saltssuch as stannous fluoride, provides significant therapeutic efficacywith decreased levels of staining and astringency, while simultaneouslyproviding reductions in supragingival calculus as compared to prior-artcompositions containing stannous fluoride alone or stannous fluoridewith stabilizing agents such as citrate.

The present oral care compositions may be formulated as single phase ordual phase compositions. One embodiment of the present inventionprovides a dual phase oral composition comprising a first compositioncomprising a fluoride ion source and a stannous ion source and a secondcomposition comprising a linear polyphosphate having an average chainlength of about 4 or more, wherein the second composition has a totalwater content of up to about 20%.

A further embodiment of the present invention relates to a single phaseoral composition comprising a fluoride ion source, a stannous ion sourceand a linear polyphosphate having an average chain length of about 4 ormore, wherein the linear polyphosphate is stabilized against hydrolyticdegradation.

The present invention also relates to single phase or dual phasecompositions comprising a fluoride ion source, a stannous ion source andan anionic polymer of MW 500 or more containing phosphonic acid ordiphosphonic acid functionalities, alone or in combination withcarboxylate functionalities, wherein the oral composition providesadequate therapeutic efficacy with minimal side effects of toothstaining and astringency while simultaneously providing cosmeticsupragingival calculus reductions.

The invention also provides a method for effective delivery ofstannous-containing compositions with minimal side effects of toothstaining or astringency and with effective tartar control byadministering to a subject a stable dentifrice composition comprising aclinically effective amount of stannous fluoride and/or other stannoussalts in combination with a polymeric mineral surface active agent, suchas a phosphate- or phosphonate-containing polymer. One method fordelivery of this improved stannous oral composition involves applicationof a dentifrice comprising two dentifrice compositions which arecontained in physically separated compartments. Another method involvesadministering to a subject a stable single-phase dentifrice composition.One embodiment of a stable single phase composition comprises apolyphosphate, or other phosphate- or phosphonate-containing anionicpolymer; a stannous source delivered from a source other than stannousfluoride; and a fluoride source, wherein the composition may have alimited total water content, depending upon stability requirements.

A preferred method for delivery of the present improvedstannous-containing compositions involves application of a dentifricecomprising two dentifrice compositions which are contained in physicallyseparated compartments. The physical separation allows for adequatestabilization of each dentifrice phase and ingredients therein. Whencombined in use, the chemical interactions of stannous (from stannousfluoride and/or other stannous salt) in one dentifrice phase with thepolymeric binding agent in a separate dentifrice phase allow appropriatedelivery of both ingredients, thus, producing full therapeutic activityalong with the provision of significant efficacy for the reduction ofdental calculus and with marked reductions in undesirable side effectsof tooth staining and astringency. The first dentifrice compositioncomprises a polyphosphate, or other phosphate or phosphonate containinganionic polymers and may have a limited total water content, while thesecond phase composition comprises stannous ions.

The present compositions comprise essential components, as well asoptional components. The essential and optional components of thecompositions of the present invention are described in the followingparagraphs.

Stannous Ion Sources

The present invention includes a stannous ion source as one essentialcomponent. The stannous ions are provided from stannous fluoride and/orother stannous salt that are added to the oral composition. Stannousfluoride has been found to help in the reduction caries, gingivitis,plaque, sensitivity, and improved breath benefits. The stannous providedin the oral composition will provide efficacy to a subject using thecomposition. Other stannous salts include stannous chloride dihydrate,stannous acetate, stannous gluconate, stannous oxalate, stannoussulfate, stannous lactate, and stannous tartrate. The preferred stannousion sources are stannous fluoride and stannous chloride dihydrate. Thecombined stannous salts will be present in an amount of from about 0.1%to about 11%, by weight of the total composition. Preferably, thestannous salts are present in an amount of from about 0.5 to about 7%,more preferably from about 1% to about 5%, and most preferably fromabout 1.5% to about 3% by weight of the total composition. Formulationsproviding efficacy typically include stannous levels, provided bystannous fluoride and stannous stabilizing salts, ranging from about3,000 ppm to about 15,000 ppm stannous ions in the total composition.Below 3,000 ppm stannous the efficacy of the stannous is not sufficient.Preferably, the stannous ion is present in an amount of about 4,000 ppmto about 12,000 ppm, more preferably 5,000 ppm to about 10,000 ppm.

Dentifrices containing stannous salts, particularly stannous fluorideand stannous chloride, are described in U.S. Pat. No. 5,004,597 toMajeti et al., incorporated herein in its entirety. Other descriptionsof stannous salts are found in U.S. Pat. No. 5,578,293 issued toPrencipe et al. and in U.S. Pat. No. 5,281,410 issued to Lukacovic etal., incorporated herein in its entirety. In addition to the stannousion source, other ingredients needed to stabilize the stannous may alsobe included, such as the ingredients described in Majeti et al. andPrencipe et al.

Fluoride Ion Sources

The oral compositions of the present invention will include as a secondessential component a soluble fluoride source capable of providingbioavailable and efficacious fluoride ions. Soluble fluoride ion sourcesinclude sodium fluoride, stannous fluoride, indium fluoride, and sodiummonofluorophosphate. Stannous fluoride is the most preferred solublefluoride source. This ingredient may serve as both a/the stannous sourceand fluoride source. Norris et al., U.S. Pat. No. 2,946,725, issued Jul.26, 1960, and Widder et al., U.S. Pat. No. 3,678,154 issued Jul. 18,1972, disclose such fluoride sources as well as others. Both patents areincorporated herein by reference in their entirety.

The present compositions may contain a soluble fluoride ion sourcecapable of providing from about 50 ppm to about 3500 ppm, and preferablyfrom about 500 ppm to about 3000 ppm of free fluoride ions. To deliverthe desired amount of fluoride ions, fluoride ion sources may be presentin the total oral composition at an amount of from about 0.1% to about5%, preferably from about 0.2% to about 1%, and more preferably fromabout 0.3% to about 0.6%, by weight of the total composition deliveredto the oral cavity.

Polymeric Mineral Surface Active Agent

The present invention includes a polymeric surface active agent (MSA).These agents show affinity for binding stannous, in particular bystannous ion chelation, as evidenced by ionic fluoride release fromstannous fluoride (SnF₂) and provision of increased ionic form offluoride upon binding of the stannous. Effective agents also showsurface reactivity toward calcium phosphate minerals, and are thusexpected to retard calculus or tartar formation. The agents may alsoprovide stain control and surface conditioning. These agents will bindthe stannous but will still enable the combined mixture to provide thedesired tartar control, stain control, and surface conditioning, withouthaving a negative effect on the efficacy of stannous fluoride for thecontrol of dental caries, oral malodor and periodontal diseasesincluding gingivitis.

The present polymeric mineral surface active agents will strongly bindstannous and retain biological reactivity while inhibiting undesirablestaining. Research has demonstrated that the binding generally occurs onthe end functions of the condensed phosphate polymers. Binding maydiffer for other effective phosphate or phosphonate containing polymersor co-polymers. Therefore, a mineral surface active agent with phosphateend groups providing the predominant binding are preferred. Even morepreferred are mineral surface active agents that have more than oneinternal phosphate group in addition to the phosphate end groups.

The polymeric mineral surface active agents that are useful in thepresent invention include polyelectrolytes such as condensedphosphorylated polymers; polyphosphonates; copolymers of phosphate- orphosphonate-containing monomers or polymers with other monomers such asethylenically unsaturated monomers and amino acids or with otherpolymers such as proteins, polypeptides, polysaccharides,poly(acrylate), poly(acrylamide), poly(methacrylate), poly(ethacrylate),poly(hydroxyalkylmethacrylate), poly(vinyl alcohol), poly(maleicanhydride), poly(maleate) poly(amide), poly(ethylene amine),poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) andpoly(vinyl benzyl chloride); carboxy-substituted polymers; and mixturesthereof. Suitable polymeric surface active agents include thecarboxy-substituted alcohol polymers described in U.S. Pat. Nos.5,292,501; 5,213,789, 5,093,170; 5,009,882; and 4,939,284; all toDegenhardt et al. and the diphosphonate-derivatized polymers in U.S.Pat. No. 5,011,913 to Benedict et al. Suitable structures includecopolymers of acrylic acid or methacrylic acid with phosphonates. Apreferred polymer is diphosphonate modified polyacrylic acid.

Suitable phosphonate-containing polymers such as shown below aredescribed in U.S. Pat. No. 5,980,776 to Zakikhani, et al., incorporatedherein in its entirety.

A preferred polymeric mineral surface active agent will be stable withionic fluoride and will not hydrolyze in high water contentformulations, thus permitting a simple single phase dentifrice ormouthrinse formulation. If the polymeric mineral surface active agentdoes not have these stability properties, it is likely that a dual phaseformulation with the polymeric mineral surface active agent separatedfrom the fluoride source will be required.

A preferred polymeric mineral surface active agent is a polyphosphate. Apolyphosphate is generally understood to consist of two or morephosphate molecules arranged primarily in a linear configuration,although some cyclic derivatives may be present. Although pyrophosphatesand tripolyphosphate are technically polyphosphates, the polyphosphatesdesired are those having around four or more phosphate molecules so thatsurface adsorption at effective concentrations produces sufficientnon-bound phosphate functions which enhance the anionic surface chargeas well as hydrophilic character of the surfaces. The pyrophosphates arediscussed separately under additional anticalculus agents. The inorganicpolyphosphate salts desired include tetrapolyphosphate andhexametaphosphate, among others. Polyphosphates larger thantetrapolyphosphate usually occur as amorphous glassy materials.Preferred in this invention are the linear “glassy” polyphosphateshaving the formula:

XO(XPO₃)_(n)X

wherein X is sodium or potassium and n averages from about 6 to about125. Preferred are polyphosphates manufactured by FMC Corporation whichare commercially known as Sodaphos (n≈6), Hexaphos (n≈13), and Glass H(n≈21). The most preferred polyphosphate is Glass H. Thesepolyphosphates may be used alone or in a combination thereof.

It is also known that polyphosphates with an average chain lengthgreater than about 4 will react with ionic fluoride in oral compositionsat ambient temperature and produce monofluorophosphate ions, in additionto altering the pH of the composition. This reaction compromises theefficacy of the oral composition and its ability to provide stable ionicfluoride and polyphosphate to the oral surfaces. It is also known thatto have stable polyphosphate, the total water content of the dentifricecomposition must be controlled to reduce the hydrolysis of thepolyphosphate. U.S. Pat. No. 5,939,052 issued to White, Jr. et al.,incorporated herein by reference in its entirety, further describes thepolyphosphates. The phosphate sources are also described in more detailin Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition,Volume 18, Wiley-Interscience Publishers (1996), incorporated herein byreference in its entirety, including all references incorporated intoKirk-Othmer.

The amount of mineral surface agent required is an effective amountwhich will bind the stannous, permit adequate antimicrobial activity,reduce dental stain and formulation astringency, and be capable ofreducing dental calculus. An effective amount of a mineral surfaceactive agent will typically be from about 1% to about 35%, preferablyfrom about 2% to about 30%, more preferably from about 5% to about 25%,and most preferably from about 6% to about 20%, by weight of the totaloral composition.

A sufficient amount of mineral surface active agent, fluoride ions, andstannous ions must be present for the composition to be effective. Informulating compositions containing phosphate, the ratio total moles ofphosphate anion to total moles of stannous ion should also becontrolled. For condensed polyphosphate having an average of 21phosphate repeating units, the ideal molar ratio has been found to be amolar ratio of phosphate anion to stannous ion of from about 0.2:1 toabout 5:1, preferably from about 0.5:1 to about 3:1, more preferablyfrom about 0.6:1 to about 2:1, and most preferably from about 0.7:1 toabout 1:1.

In addition to binding stannous ions effectively, the polymeric mineralsurface active agent has been found to solubilize insoluble salts. Forexample, Glass H polyphosphate has been found to solubilize insolublestannous salts as well as stannous oxides and hydroxides.

Aqueous Carriers

In preparing the present compositions, it is desirable to add one ormore aqueous carriers to the compositions. Such materials are well knownin the art and are readily chosen by one skilled in the art based on thephysical and aesthetic properties desired for the compositions beingprepared. These aqueous carriers may be included at levels which do notprevent the interaction between the stannous and the polymeric mineralsurface active agent. The amounts of the polymeric mineral surfaceactive agent, stannous, and fluoride may be adjusted if necessary tocompensate for the additional carriers. Aqueous carriers typicallycomprise from about 50% to about 99%, preferably from about 70% to about98%, and more preferably from about 90% to about 95%, by weight of theoral composition.

Total Water Content

Water employed in the preparation of commercially suitable oralcompositions should preferably be of low ion content and free of organicimpurities. In the oral composition, water will generally comprise fromabout 5% to about 95%, and preferably from about 10% to about 50%, byweight of the composition herein. This water content may be in a singlephase oral composition or may be the resulting total water content of adual phase oral composition. If the oral composition comprises apolyphosphate having an average chain length of about 4 or more, thecomposition or phase containing the polyphosphate will comprise a lowerlevel of water, generally up to about 20% total water. Preferably, thetotal water content is from about 2% to about 20%, more preferably fromabout 4% to about 15%, and most preferably from about 5% to about 12%,by weight of the oral composition. The amounts of water include the freewater which is added plus that which is introduced with other materials,such as with sorbitol, silica, surfactant solutions, and/or colorsolutions.

Buffering Agent

The present compositions may contain a buffering agent. Bufferingagents, as used herein, refer to agents that can be used to adjust thepH of the compositions to a range of about pH 3.0 to about pH 10. Thephase of the oral composition containing stannous will typically have aslurry pH of from about 3.0 to about 7.0, preferably from about 3.25 toabout 6.0, and more preferably from about 3.5 to about 5.5. The phasecontaining the polymeric mineral surface active agent will typicallyhave a slurry pH of from about 4.0 to about 10, preferably from about4.5 to about 8, and more preferably from about 5.0 to about 7.0. An oralcomposition containing both stannous and a polymeric mineral surfaceactive agent in a single phase will typically have a pH of from about 4to about 7, preferably from about 4.5 to about 6.5, and more preferablyfrom about 5 to about 6.

The buffering agents include alkali metal hydroxides, carbonates,sesquicarbonates, borates, silicates, phosphates, imidazole, andmixtures thereof. Specific buffering agents include monosodiumphosphate, trisodium phosphate, sodium benzoate, benzoic acid, sodiumhydroxide, potassium hydroxide, alkali metal carbonate salts, sodiumcarbonate, imidazole, pyrophosphate salts, citric acid, and sodiumcitrate. Preferred buffers would be those that control the pH in thetarget range without complexing stannous ions. Preferred bufferingagents include acetic acid, sodium acetate, citric acid, sodium citrate,benzoic acid and sodium benzoate. Buffering agents are used at a levelof from about 0.1% to about 30%, preferably from about 1% to about 10%,and more preferably from about 1.5% to about 3%, by weight of thepresent composition.

Additional Anticalculus Agents

Optional agents to be used in combination with the stannous fluoridebinding mineral surface active agent include such materials known to beeffective in reducing mineral deposition related to calculus formation.These agents may be included at levels, which do not prevent theformation of the stannous fluoride/stannous fluoride binding mineralsurface active agent complex. Agents included are pyrophosphates,tripolyphosphates, and synthetic anionic polymers includingpolyacrylates and copolymers of maleic anhydride or acid and methylvinyl ether, such as Gantrez as described in U.S. Pat. No. 4,627,977 toGaffar et al., and polyamino propane sulfonic acid (AMPS). Also includedare zinc citrate trihydrate, diphosphonates such as EHDP and AHP andpolypeptides such as polyaspartic and polyglutamic acids, and mixturesthereof.

Abrasive Polishing Materials

An abrasive polishing material may also be included in the oralcompositions. The abrasive polishing material contemplated for use inthe compositions of the present invention can be any material which doesnot excessively abrade dentin. Additionally, the abrasive polishingmaterial should be formulated in the oral composition so that it doesnot compromise the stability of the stannous fluoride. For example, in adual phase oral composition, the abrasive polishing material ispreferably in a separate phase from the fluoride ion source and stannousion source.

Typical abrasive polishing materials include silicas including gels andprecipitates; aluminas; phosphates including orthophosphates,polymetaphosphates, and pyrophosphates; and mixtures thereof. Specificexamples include dicalcium orthophosphate dihydrate, calciumpyrophosphate, tricalcium phosphate, calcium polymetaphosphate,insoluble sodium polymetaphosphate, hydrated alumina, beta calciumpyrophosphate, calcium carbonate, and resinous abrasive materials suchas particulate condensation products of urea and formaldehyde, andothers such as disclosed by Cooley et al in U.S. Pat. No. 3,070,510,issued Dec. 25, 1962, incorporated herein by reference. Mixtures ofabrasives may also be used. If the oral composition or particular phasecomprises a polyphosphate having an average chain length of about 4 ormore, calcium containing abrasives and alumina are not preferredabrasives. The most preferred abrasive is silica.

Silica dental abrasives of various types are preferred because of theirunique benefits of exceptional dental cleaning and polishing performancewithout unduly abrading tooth enamel or dentine. The silica abrasivepolishing materials herein, as well as other abrasives, generally havean average particle size ranging between about 0.1 to about 30 microns,and preferably from about 5 to about 15 microns. The abrasive can beprecipitated silica or silica gels such as the silica xerogels describedin Pader et al., U.S. Pat. No. 3,538,230, issued Mar. 2, 1970, andDiGiulio, U.S. Pat. No. 3,862,307, issued Jan. 21, 1975, bothincorporated herein by reference. Preferred are the silica xerogelsmarketed under the trade name “Syloid” by the W.R. Grace & Company,Davison Chemical Division. Also preferred are the precipitated silicamaterials such as those marketed by the J. M. Huber Corporation underthe trade name, “Zeodent”, particularly the silica carrying thedesignation “Zeodent 119”. The types of silica dental abrasives usefulin the toothpastes of the present invention are described in more detailin Wason, U.S. Pat. No. 4,340,583, issued Jul. 29, 1982, incorporatedherein by reference. Silica abrasives are also described in Rice, U.S.Pat. Nos. 5,589,160; 5,603,920; 5,651,958; 5,658,553; and 5,716,601;herein incorporated by reference. The abrasive in the oral compositioncompositions described herein is generally present at a level of fromabout 6% to about 70% by weight of the composition. Preferably, oralcompositions contain from about 10% to about 50% of abrasive, by weightof the oral composition.

Peroxide Source

The present invention may include a peroxide source in the composition.The peroxide source is selected from the group consisting of hydrogenperoxide, calcium peroxide, urea peroxide, and mixtures thereof. Thepreferred peroxide source is calcium peroxide. Preferably, to maximizestability, the peroxide source is not in the same phase as the stannousion source. The following amounts represent the amount of peroxide rawmaterial, although the peroxide source may contain ingredients otherthan the peroxide raw material. The present composition may contain fromabout 0.01% to about 10%, preferably from about 0.1% to about 5%, morepreferably from about 0.2% to about 3%, and most preferably from about0.3% to about 0.8% of a peroxide source, by weight of the oralcomposition.

Alkali Metal Bicarbonate Salt

The present invention may also include an alkali metal bicarbonate salt.Alkali metal bicarbonate salts are soluble in water and unlessstabilized, tend to release carbon dioxide in an aqueous system. Sodiumbicarbonate, also known as baking soda, is the preferred alkali metalbicarbonate salt. The alkali metal bicarbonate salt also functions as abuffering agent. Because of the pH at which alkali metal bicarbonatesalts buffer, the bicarbonate salt is preferably in a phase separatefrom the stannous ion source. The present composition may contain fromabout 0.5% to about 50%, preferably from about 0.5% to about 30%, morepreferably from about 2% to about 20%, and most preferably from about 5%to about 18% of an alkali metal bicarbonate salt, by weight of the oralcomposition.

Additional Aqueous Carriers

The present invention compositions are in the form of toothpastes,dentifrices, topical oral gels, mouthrinse, denture product,mouthsprays, lozenges, oral tablets or chewing gums and typicallycontain some thickening material or binders to provide a desirableconsistency. The amount and type of the thickening material will dependupon the form of the product. Preferred thickening agents arecarboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, and watersoluble salts of cellulose ethers such as sodium carboxymethylcelluloseand sodium hydroxyethyl cellulose. Natural gums such as gum karaya,xanthan gum, gum arabic, and gum tragacanth can also be used. Colloidalmagnesium aluminum silicate or finely divided silica can be used as partof the thickening agent to further improve texture. Thickening agentscan be used in an of amount from about 0.1% to about 15%, by weight ofthe oral composition.

Another optional component of the compositions desired herein is ahumectant. The humectant serves to keep oral compositions from hardeningupon exposure to air and certain humectants can also impart desirablesweetness of flavor to toothpaste compositions. Suitable humectants foruse in the invention include glycerin, sorbitol, polyethylene glycol,propylene glycol, xylitol, and other edible polyhydric alcohols. Thehumectant generally comprises from about 0% to 70%, and preferably fromabout 15% to 55%, by weight of the oral composition.

The present compositions may also comprise surfactants, also commonlyreferred to as sudsing agents. Suitable surfactants are those which arereasonably stable and foam throughout a wide pH range. The surfactantmay be anionic, nonionic, amphoteric, zwitterionic, cationic, ormixtures thereof. Anionic surfactants useful herein include thewater-soluble salts of alkyl sulfates having from 8 to 20 carbon atomsin the alkyl radical (e.g., sodium alkyl sulfate) and the water-solublesalts of sulfonated monoglycerides of fatty acids having from 8 to 20carbon atoms. Sodium lauryl sulfate and sodium coconut monoglyceridesulfonates are examples of anionic surfactants of this type. Othersuitable anionic surfactants are sarcosinates, such as sodium lauroylsarcosinate, taurates, sodium lauryl sulfoacetate, sodium lauroylisethionate, sodium laureth carboxylate, and sodium dodecylbenzenesulfonate. Mixtures of anionic surfactants can also be employed.Many suitable anionic surfactants are disclosed by Agricola et al., U.S.Pat. No. 3,959,458, issued May 25, 1976, incorporated herein in itsentirety by reference. Nonionic surfactants which can be used in thecompositions of the present invention can be broadly defined ascompounds produced by the condensation of alkylene oxide groups(hydrophilic in nature) with an organic hydrophobic compound which maybe aliphatic or alkyl-aromatic in nature. Examples of suitable nonionicsurfactants include poloxamers (sold under trade name Pluronic),polyoxyethylene, polyoxyethylene sorbitan esters (sold under trade nameTweens), Polyoxyl 40 hydrogenated castor oil, fatty alcohol ethoxylates,polyethylene oxide condensates of alkyl phenols, products derived fromthe condensation of ethylene oxide with the reaction product ofpropylene oxide and ethylene diamine, ethylene oxide condensates ofaliphatic alcohols, long chain tertiary amine oxides, long chaintertiary phosphine oxides, long chain dialkyl sulfoxides, and mixturesof such materials. The nonionic surfactant poloxamer 407 is one of themost preferred surfactant because the poloxamer has been discovered tohelp reduce the astringency of the stannous. The amphoteric surfactantsuseful in the present invention can be broadly described as derivativesof aliphatic secondary and tertiary amines in which the aliphaticradical can be a straight chain or branched and wherein one of thealiphatic substituents contains from about 8 to about 18 carbon atomsand one contains an anionic water-solubilizing group, e.g., carboxylate,sulfonate, sulfate, phosphate, or phosphonate. Other suitable amphotericsurfactants are betaines, specifically cocamidopropyl betaine. Mixturesof amphoteric surfactants can also be employed. Many of the suitablenonionic and amphoteric surfactants are disclosed by Gieske et al., U.S.Pat. No. 4,051,234, issued Sep. 27, 1977, incorporated herein byreference in its entirety. The present composition typically comprisesone or more surfactants each at a level of from about 0.25% to about12%, preferably from about 0.5% to about 8%, and most preferably fromabout 1% to about 6%, by weight of the composition.

Titanium dioxide may also be added to the present composition. Titaniumdioxide is a white powder which adds opacity to the compositions.Titanium dioxide generally comprises from about 0.25% to about 5%, byweight of the composition.

Coloring agents may also be added to the present composition. Thecoloring agent may be in the form of an aqueous solution, preferably 1%coloring agent in a solution of water. Color solutions generallycomprise from about 0.01% to about 5%, by weight of the composition.

A flavor system can also be added to the compositions. Suitableflavoring components include oil of wintergreen, oil of peppermint, oilof spearmint, clove bud oil, menthol, anethole, methyl salicylate,eucalyptol, cassia, 1-menthyl acetate, sage, eugenol, parsley oil,oxanone, alpha-irisone, marjoram, lemon, orange, propenyl guaethol,cinnamon, vanillin, ethyl vanillin, heliotropine, 4-cis-heptenal,diacetyl, methyl-para-tert-butyl phenyl acetate, and mixtures thereof.Coolants may also be part of the flavor system. Preferred coolants inthe present compositions are the paramenthan carboxyamide agents such asN-ethyl-p-menthan-3-carboxamide (known commercially as “WS-3”) andmixtures thereof. A flavor system is generally used in the compositionsat levels of from about 0.001% to about 5%, by weight of thecomposition.

Sweetening agents can be added to the compositions. These includesaccharin, dextrose, sucrose, lactose, xylitol, maltose, levulose,aspartame, sodium cyclamate, D-tryptophan, dihydrochalcones, acesulfame,and mixtures thereof. Various coloring agents may also be incorporatedin the present invention. Sweetening agents and coloring agents aregenerally used in toothpastes at levels of from about 0.005% to about5%, by weight of the composition.

The present invention may also include other agents in addition to thestannous to provide antimicrobial benefits. These agents may be includedat levels which do not prevent the interaction between stannous and thepolymeric mineral surface active agent. Included among suchantimicrobial agents are water insoluble non-cationic antimicrobialagents such as halogenated diphenyl ethers, phenolic compounds includingphenol and its homologs, mono and poly-alkyl and aromatic halophenols,resorcinol and its derivatives, bisphenolic compounds and halogenatedsalicylanilides, benzoic esters, and halogenated carbanilides. The watersoluble antimicrobials include quaternary ammonium salts andbis-biquanide salts, among others. Triclosan monophosphate is anadditional water soluble antimicrobial agent. The quaternary ammoniumagents include those in which one or two of the substitutes on thequaternary nitrogen has a carbon chain length (typically alkyl group)from about 8 to about 20, typically from about 10 to about 18 carbonatoms while the remaining substitutes (typically alkyl or benzyl group)have a lower number of carbon atoms, such as from about 1 to about 7carbon atoms, typically methyl or ethyl groups. Dodecyl trimethylammonium bromide, tetradecylpyridinium chloride, domiphen bromide,N-tetradecyl-4-ethyl pyridinium chloride, dodecyl dimethyl(2-phenoxyethyl) ammonium bromide, benzyl dimethylstearyl ammoniumchloride, cetyl pyridinium chloride, quaternized5-amino-1,3-bis(2-ethyl-hexyl)-5-methyl hexa hydropyrimidine,benzalkonium chloride, benzethonium chloride and methyl benzethoniumchloride are exemplary of typical quaternary ammonium antibacterialagents. Other compounds are bis[4-(R-amino)-1-pyridinium] alkanes asdisclosed in U.S. Pat. No. 4,206,215, issued Jun. 3, 1980, to Bailey,incorporated herein by reference. Other antimicrobials such as copperbisglycinate, copper glycinate, zinc citrate, and zinc lactate may alsobe included. Also useful are enzymes, including endoglycosidase, papain,dextranase, mutanase, and mixtures thereof. Such agents are disclosed inU.S. Pat. No. 2,946,725, Jul. 26, 1960, to Norris et al. and in U.S.Pat. No. 4,051,234, to Gieske et al., incorporated herein by reference.Specific antimicrobial agents include chlorhexidine, triclosan,triclosan monophosphate, and flavor oils such as thymol.

Triclosan and other agents of this type are disclosed in U.S. Pat. No.5,015,466, issued to Parran, Jr. et al. and U.S. Pat. No. 4,894,220, toNabi et al., incorporated herein by reference. The water insolubleantimicrobial agents, water soluble agents, and enzymes may be presentin either the first or second oral compositions if there are two phases.These agents may be present at levels of from about 0.01% to about 1.5%,by weight of the oral composition.

A dentifrice composition may be a paste, gel, or any configuration orcombination thereof. If a dual phase dentifrice is desired, the firstand second dentifrice compositions will be physically separated in adentifrice dispenser. It is generally preferred that the firstdentifrice composition be a paste and the second dentifrice compositionbe a gel. The dispenser may be a tube, pump, or any other containersuitable for dispensing toothpaste. Dual compartment packages suitablefor this purpose are described in U.S. Pat. No. 4,528,180; U.S. Pat. No.4,687,663; and 4,849,213, all to Shaeffer, all incorporated herein intheir entirety. The dispenser will deliver approximately equal amountsof each dentifrice composition through an opening. The compositions mayintermix once dispensed. Alternatively, the oral formulation may bedelivered from a kit containing two separate dispensers which are usedto deliver two dentifrice compositions that are both usedsimultaneously.

EFFICACY MEASURES

Overall performance of the present compositions may be defined in termsof an efficacy score/stain score ratio, wherein efficacy is measuredusing the in vitro Plaque Glycolysis and Regrowth Model (i-PGRM), andstain is measured using the in vitro Pellicle Tea Stain Model (i-PTSM).The present compositions provide an efficacy score to stain score ratioof at least 1.2, which represents a realistic improvement in thatsufficient therapeutic efficacy is maintained while achieving areduction in staining. Improvement in formulation astringency is definedas greater than 50% increase in formulation mouth feel parameters suchas dry mouth, and clean mouth indices as defined in controlled consumertesting. Effectiveness for control of supragingival calculus is definedby activity in prevention of plaque calcification using the ModifiedPlaque Growth and Mineralization assay.

Antimicrobial Activity

The stannous ion concentration and bioavailability required for theprovision of therapeutic actions may differ for different clinicalactions, for example, caries vs. gingivitis. However, it is critical toestablish a minimum antimicrobial activity level, since the therapeuticactivity of stannous can be compromised below this level. It isespecially important to maintain efficacy in compositions whereinbinding of stannous occurs, since stannous binding can easily lead toloss of antimicrobial activity. Herein, the minimum efficacy provided bythe stannous ion source is defined in terms of effects in producingmetabolic inhibition of dental plaque bacterial biofilms, which areresponsible for numerous undesirable intraoral conditions. Efficacy isthus defined in terms of a noticeable and significant reduction in insitu plaque metabolism as measured using the in vitro Plaque Glycolysisand Regrowth Model (i-PGRM), developed in our laboratories. The i-PGRMhas been demonstrated to provide an excellent correlation tobioavailability of stannous fluoride required to produce clinicalantimicrobial, antigingivitis and antiplaque activity of oralcompositions containing stannous fluoride. The efficacy of stannouscontaining compositions for gingivitis can be directly compared to astannous-containing dentifrice formulation such as described in U.S.Pat. No. 5,004,597 to Majeti, et al. and shown in Example II below asComparative Example or to a currently marketed dentifrice containingstannous fluoride, Crest Gum Care.

The i-PGRM is a technique where plaque is grown from human saliva, andtreated with agents designed to produce various levels of antimicrobialactivity. The purpose of this technique is to provide a simple and quickmethod for determining if compounds have a direct effect on themetabolic pathways that plaque microorganisms utilize for the productionof toxins which adversely affect gingival health. In particular, themodel focuses on the production of organic acids including lactic,acetic, propionic, and butyric. This method utilizes plaque grown onpolished glass rods which have been dipped in saliva overnight, soybroth and sucrose for 6 hours, and saliva again overnight. The plaquemass grown on the glass rods is then treated for 1 minute with a 3:1water to dentifrice slurry. The mass is then placed in a soybroth/sucrose solution for 6 hours and the pH of the incubation solutionis measured at the end of the 6 hours. Thus, there are measures ofpre-incubation pH and post incubation pH for both test formulations andcontrols. This testing is typically done with a number of replicates tominimize experimental variances, and a mean pH is calculated from thereplicates. Due to strong reactivity with saccharolytic organisms,compositions containing high levels of bioavailable stannous producesignificant inhibition of plaque acid generation in the i-PGRM assay.This enables formulation variations to be compared for stability andbioavailability of stannous with relative ease.

Stannous fluoride and/or other stannous salts are found in the oralcompositions described herein in an effective amount to provide adesired i-PGRM score. The desired i-PGRM score is measured relative tonon-stannous containing formulations (negative control) and tostannous-containing formulations (positive control) such as described inU.S. Pat. No. 5,004,597 to Majeti et al. Most preferable i-PGRM scoresare significantly different from placebo controls and ideally similar tothose provided by conventional stannous fluoride compositions proveneffective for reducing plaque and gingivitis. Research has demonstratedthat effective gingivitis efficacy can be anticipated for compositionsproviding at least about 60%, preferably at least about 70%, and morepreferably at least about 80% of an effective stannous-containingdentifrice such as shown in Example II, Comparative Example below.

The i-PGRM score is calculated according to the formula:${\text{-}{PGRM}\quad {Score}} = {100\% \times \frac{\left( {{{Test}\quad {product}\quad {mean}\quad {pH}} - {{Non}\text{-}{Stannous}\quad {Control}\quad {mean}{\quad \quad}{pH}}} \right)}{\left( {{{Stannous}\quad {Control}\quad {mean}\quad {pH}} - {{Non}\text{-}{Stannous}\quad {Control}\quad {mean}\quad {pH}}} \right)}}$

The mean pH values refer to incubation media pH's obtained followingtreatment and sucrose challenge. The non-stannous control plaque samplesproduce large amounts of acid, and hence their pH's are lower than thatof plaque samples treated with the positive control (stabilized stannousfluoride dentifrice as shown in Example II, Comparative Example). Theeffectiveness of a formulation prepared from the combination of astannous ion source and polymeric mineral surface active agent willideally be comparable to the stannous-containing control, and henceideal i-PGRM score should approach 100%.

Staining Reduction

Tooth staining is a common undesirable side effect of the use ofstannous fluoride compositions. Improved stannous fluoride dentifricesdescribed herein provide reduced dental stain formation resulting frommore efficient stannous delivery from stannous bound to the polymericmineral surface active agent. The staining of the tooth surfacetypically caused by stannous is measured in the clinical situation byusing a stain index such as the Lobene or Meckel indices described inthe literature. The present inventors have also developed an in vitrostaining model which provides quantitative estimates for stannousfluoride formulation staining potential which correlate well withclinical observations. Formulations can thus be tested in advance ofclinical examination using these methods.

The in-vitro Pellicle Tea Stain Model (i-PTSM) is a technique where anin vitro plaque biomass is grown on glass rods from pooled humanstimulated saliva over the course of three days. The plaque biomass istreated with 3:1 water to dentifrice supernatants, where abrasive andinsoluble solids have been removed via centrifugation, to determinepotential dental staining levels of the various agents. The purpose ofthis technique is to provide a simple and quick method for determiningif compounds have a direct effect on the amount of dental plaque stain.This method utilizes plaque grown on polished glass rods from pooledhuman saliva with treatments of 5 minutes each, followed by a 10 minutetea treatment. The treatment regimen is repeated at lest three timesbefore the plaque mass is digested off the rods, filtered and absorbanceat 380 nm is measured. This testing is typically done with a number ofreplicates to minimize experimental variances, and a mean absorbance iscalculated from the replicates.

The present inventors have found that the stain, which is typicallyproduced by effective stannous fluoride is reduced by combining thestannous fluoride with one or a mixture of the polymeric surface activeagents discussed above. The benefit of reducing the staining caused bystannous is achieved with the present compositions without significantlycompromising the efficacy of the stannous, fluoride, and polymericsurface agent. The amount of staining resulting from the oralcompositions of the present invention is significantly lower than theamount of staining resulting from typical dentifrices containingstannous. The term “reduced” as used herein means a statisticallysignificant reduction. Therefore, reducing the staining of stannousmeans that the amount of stain is statistically significantly reducedrelative to a stannous-containing positive control. Not reducing theefficacy of the stannous means the efficacy of the stannous is notstatistically significantly reduced relative to a stannous-containingpositive control. Alternatively, stain may be measured relative totypical oral compositions, which do not contain stannous fluoride oranother antimicrobial agent which is known to stain. Therefore, thecompositions may be measured relative to very little to no stain.

The i-PTSM score can be calculated from this staining assay according tothe formula:${\text{-}{PTSM}\quad {Score}} = {100\% \times \frac{{Test}\quad {Product}\quad {Mean}\quad {Absorbance}}{\left( {{Stannous}\quad {Control}\quad {Mean}\quad {Absorbance}} \right)}}$

The mean absorbance values refer to digested plaque colorimetric valuesobtained following dentifrice treatments and tea rinsing challenge. Thestannous control used is typically a high staining stannous fluorideformulation such as illustrated in Example II, Comparative Examplebelow. The stannous control samples produce large amounts of teaabsorption and hence increased colorimetric absorbance. Thus, the i-PTSMscore is a measure of the relative level of staining. The lower thescore, the lower the level of staining. The combination of a stannousion source and polymeric mineral surface active agent provides areduction in staining and will ideally have a i-PTSM score of less thanabout 75%, preferably less than 60%, more preferably less than 50%, mostpreferably less than 25%.

Ratio of i-PGRM Score to i-PTSM Score

A key descriptor of the improvement in stannous compositions providedherein is the ratio of efficacy of stannous in comparison to stainingpotential, these being key consumer concerns. The effectiveness of theoral composition of the present invention will be measured by a ratio ofi-PGRM score to i-PTSM score.

The ratio of i-PGRM score to i-PTSM score is calculated according to theformula:

Ratio=i-PGRM score/i-PTSM score

In accordance with the present invention, the ratio developed usingthese methods should be at least about 1.2 for significant improvementsin stannous formulation efficacy relative to tooth staining sideeffects. The ratio is preferably above about 1.3, more preferably aboveabout 1.5, and most preferably above about 2.0. If there is little to nostain occurring, the ratio approaches infinity, which is preferred.

Binding of Stannous

As discussed above, effective delivery of improved stannous and stannousfluoride reactivity (efficacy with reduced side effects) requiressignificant in situ binding or complexation of stannous ion with themineral surface active (MSA) polymer. In mixed compositions containingstannous fluoride, evidence of significant binding of stannous isreadily observed by potentiometric detection of available ionicfluoride. For example, binding of stannous with polyphosphate MSA ligandresults in exchange of fluoride from stannous fluoride and release asionic fluoride into solution. Relevant measures of stannous binding canbe assessed by this technique because fluoride is the strongest ligandin the system after the MSA binding agent. Thus, fluoride release isillustrative of stannous binding by the polymeric MSA under theseconditions.

The binding chemistry occurring is illustrated in the followingexperiment using the dentifrice composition described in Example 1herein. In this experiment, the stannous fluoride/stannous chloridetoothpaste phase (second dentifrice composition) was slurried at a 1:2.5ratio with distilled water (representing ½ dilution in real brushing).In like manner, a paste phase (first dentifrice composition) wasslurried. This paste phase included either a placebo (conventional)dentifrice control with no MSA polyphosphate or a paste phase containing15% Glass H polyphosphate according to Example I, first dentifriceformulation A. The two slurries were mixed and ionic fluoride readingsmade by ISE fluoride electrode on a digital pH meter. Following reading,a standard addition of 10 and 100 fold excess ionic fluoride (fromneutral NaF) was added to the mixed slurries enabling calibration withinmatrix through the standard additions technique. Results shown belowillustrate stannous binding by polyphosphate as added to the paste inthese mixed compositions.

Free Ionic Fluoride in Formulation Mixed 20% Slurry Theoretical FRelease from 1100 ppm Total ˜190 ppm Fluoride in System NaF ControlPaste (all ionic F) - Total  185 ppm Fluoride = 1100 ppm SnF₂ Slurry(Comparative Example Mixed as  42 ppm Phase 1 and Phase 2) TotalFluoride = 1100 ppm Mixed Polyphosphate Stannous Fluoride  195 ppmSystem Total Fluoride = 1100 ppm

Results show significant and complete stannous binding by MSA informulations according to this invention. Note that only about 25% offluoride is available as ionic fluoride in conventional compositions,which demonstrates the strength of stannous binding to fluoride ions.Likewise, evidence of significant stannous ion binding can bedemonstrated in single phase compositions, although in these casesbinding may occur in situ within compositions prior to dilution.Importantly, stannous binding to mineral surface active polymeric agentsoccurs within the oral cavity on brushing, that is, when the compositionis diluted with saliva during the course of toothbrushing.

Astringency Reduction

Astringency is an additional side effect of many stannous containingcompositions which is significantly improved in the present compositionscomprising the polymeric mineral surface active agents in combinationwith stannous and fluoride. The astringency of formulations can bemeasured in intraoral panels, where subjects assess mouth conditionbefore and after tooth brushing with the test formulations. In thesestudies, time dependent studies can be made of dentifrice effects onconsumer subjective responses. In one protocol, panelists began aconditioning series by having teeth cleaned with vigorous self oralhygiene including brushing for two three minute periods, flossing anddisclosing to ensure complete plaque removal. Subjects are then assignedtheir test product and instructed to brush with twice per day as usual.For these tests, subjects reported in the morning to a clinic prior toany oral hygiene or food or beverage consumption. Panelists are thenasked to fill out a subjective mouth feel assessment questionnaireincluding questions on tooth clean feeling, smooth teeth feeling andclean mouth feeling as well as assessments of mouth moisture. Paneliststhen brushed for one minute with assigned oral product. At this point,before lunch and before dinner (late p.m.) subjects again filled outsubjective mouth feel questionnaire. Results of these tests show thatthe present formulations containing stannous salts in combination with apolymeric mineral surface active agent such as the Glass H polyphosphateproduce a marked improvement in formulation astringency post brushing.Astringency is reduced compared to conventional stannous formulationswithout the polymeric surface active agent. Acceptability of the presentformulation is comparable to conventional sodium fluoride (NaF) andtartar control dentifrices respectively.

Reduction and Control of Calculus

The provision of anticalculus benefits is another desirable aspect ofthe present stannous fluoride formulations. Anticalculus activity can bepredicted from mineral surface activity measurements and the applicationof plaque growth and mineralization assays. The present compositionsinclude certain polymeric mineral surface active agents, such aspolyphosphates that bind stannous ions. Preferred compositions containmineral surface active phosphate polymers with significant affinity fordental surfaces, which are comprised of calcium hydroxyapatites.Preferred polymeric surface active agents will include phosphatepolymers which produce significant reductions in calcium phosphatemineralization as established in controlled mineralization assays.Polyphosphates (in particular linear polyphosphates with average chainlengths greater than about 4) have been found by the present inventorsto produce superior activity and substantivity to oral surfaces comparedto pyrophosphate and some other commonly used dental cleaningingredients. The increased activity and substantivity translate intosignificant improvements in the prevention of dental stains andsupragingival calculus and in the non-abrasive removal of dental stains.Without wishing to be bound by theory, it is believed that thepolyphosphates prevent formation of supragingival calculus byessentially disrupting the mineralization process, which is theformation of hard calcium phosphate mineral deposits on that thepolyphosphates prevent formation of supragingival calculus byessentially disrupting the mineralization process, which is theformation of hard calcium phosphate mineral deposits on tooth enamel. Bybinding to tooth surfaces, polyphosphates disrupt the mineral buildingprocess, because their structures do not adequately fit the developingmineral lattice, which becomes the calculus.

Method of Treatment

The present invention also relates to a method of treating gingivitisand plaque with reduced staining, by using the present compositionscomprising a stannous ion source, a fluoride ion source and particularpolymeric mineral surface active agents. Additionally provided aremethods of providing oral compositions, which have caries, gingivitis,plaque, tartar, stain, sensitivity, aesthetics, breath, mouthfeel, andcleaning benefits. The benefits of these compositions may increase overtime when the composition is repeatedly used. Specifically, the methodof treatment will include reducing the gingivitis and plaque, asmeasured by the i-PGRM, while reducing the staining caused by oralcomposition containing stannous, as measured by the i-PTSM. The ratio ofthe i-PGRM score to i-PTSM stain model score is above about 1.2.

The present invention also relates to methods for reducing the incidenceof calculus on dental enamel and to methods for providing desirablemouth aesthetic benefits including reduced astringency and oral surfaceconditioning effects. The benefits of these compositions may increaseover time when the composition is repeatedly used.

Methods of treatment include preparing an oral composition containingthe stannous ion source, the fluoride source and the polymeric mineralsurface active agent and administering the composition to the subject.Administering to the subject may be defined as having the oralcomposition contact the tooth surfaces of the subject by brushing with adentifrice or rinsing with a dentifrice slurry. Administration may alsobe by contacting the topical oral gel, mouthrinse, denture product,mouthspray, oral tablet, lozenge, or chewing gum with the toothsurfaces. The subject may be any person or lower animal whose toothsurfaces contact the oral composition.

It should be understood that the present invention relates not only tomethods for delivering the present polymeric surface active agentcontaining compositions to the oral cavity of a human, but also tomethods of delivering these compositions to the oral cavity of otheranimals, e.g., household pets or other domestic animals, or animals keptin captivity.

For example, a method of treatment may include a person brushing a dog'steeth with one of the dentifrice compositions. Another example wouldinclude the rinsing of a cat's mouth with an oral composition for asufficient amount of time to see a benefit. Pet care products such aschews and toys may be formulated to contain the present oralcompositions. The composition including the polymeric surface activeagent is incorporated into a relatively supple but strong and durablematerial such as rawhide, ropes made from natural or synthetic fibers,and polymeric articles made from nylon, polyester or thermoplasticpolyurethane. As the animal chews, licks or gnaws the product, theincorporated active elements are released into the animal's oral cavityinto a salivary medium, comparable to an effective brushing or rinsing.

Examples & Method of Manufacturing

The following examples and descriptions further clarify embodimentswithin the scope of the present invention. These examples are givensolely for the purpose of illustration and are not to be construed aslimitations of the present invention as many variations thereof arepossible without departing from the spirit and scope.

EXAMPLE I

Example I illustrates dual phase dentifrice compositions incorporatingsodium polyphosphate (Glass H supplied by FMC Corporation, n=21 unitcondensed phosphate polymer) in the First Dentifrice composition andincorporating stannous fluoride and other stannous salts in the SecondDentifrice composition.

Formula Formula Formula Ingredient 1a 2a 3a Formula 4a First DentifriceCompositions Carboxymethycellulose 0.500 0.200 0.200 0.300 Water 2.210 —— 1.400 Flavor 1.500 1.100 1.100 1.100 Glycerin 29.890 45.550 43.55039.850 Polyethylene Glycol 1.500 — — 6.000 Polyoxyethylene 0.200 — — —Propylene Glycol 8.000 — — — Sodium Lauryl 10.000 8.000 10.000 6.000Sulfate^((a)) Silica 15.000 18.150 18.150 26.000 Polyoxyl 40Hydrogenated 2.500 — — Castor Oil Benzoic Acid 0.600 — — 0.300 SodiumBenzoate 0.600 — — 0.300 Sodium Saccharin 0.400 0.400 0.400 0.350Titanium Dioxide 1.000 0.500 0.500 0.400 Glass H Polyphosphate 25.80026.000 26.000 18.000 Xanthan Gum 0.300 0.100 0.100 — Formula FormulaFormula Ingredient 1b 2b 3B Formula 4b Second Dentifrice CompositionsPolyoxyethylene — 0.200 — — Water 21.840 49.0388 56.348 12.000 Flavor1.500 1.300 1.200 1.100 FD&C Blue #1 Dye Sol'n 0.300 0.300 0.100 0.500Glycerin 30.550 22.000 22.000 — Polyethylene Glycol — — — 6.000Poloxamer 407 15.500 17.500 16.500 7.000 Sodium Lauryl Sulfate^((a)) —2.500 — 7.500 Silica 23.000 — — 20.000 Sodium Gluconate 3.290 2.9401.840 4.135 Stannous Fluoride 0.908 1.062 1.062 — Stannous Chloride —1.510 0.370 — Stannous Sulfate 2.016 — — 2.851 Sodium Hydroxide^((b))0.746 0.600 0.280 0.900 Sodium Saccharin 0.350 0.400 0.300 0.400 SodiumFluoride — — — 0.486 Sorbitol^((c)) — — — 35.528 Xanthan Gum — 0.850 —1.100 Hydroxyethyl Cellulose — — — 0.500 ^((a))27.9% solution ^((b))50%solution ^((c))70% solution

The first dentifrice compositions are prepared as follows. Add the waterand/or sodium lauryl sulfate solution and water soluble salts to mainmixing vessel. In a separate vessel, disperse thickeners in glycerin.Add this glycerin slurry to the mixing vessel, mixing well. Add thepropylene glycol and polyethylene glycol to the mixing vessel and mixuntil well dispersed. Next add titanium dioxide and silica. Mix well.Cool the mixing vessel to less than 30° C. and add the polyphosphate.Mix until homogeneous.

The second dentifrice compositions are prepared as follows. Add glycerinand/or to the main mix tank. Add thickeners, non-ionic surfactants,flavors, stannous salts and/or fluoride salts to the main mix vessel.Mix/homogenize until well dispersed and homogeneous. Add water to themain mix tank and mix/homogenize until the salts and surfactants havedissolved, the thickeners are hydrated and the mix is homogeneous. Addsodium hydroxide and color and mix well. Add sodium lauryl solution andmix until homogeneous. Cool batch to less than 30° C.

Measured i-PGRM scores, i-PTSM scores and i-PGRM/i-PTSM ratios are shownbelow for various combinations of dual phase formulations containingstannous ions, fluoride sources and polyphosphate mineral surface activeagent.

Test Method 1a + 1b 2a + 2b 3a + 3b 4a + 4b i-PGRM Score 77.9 78.1 92.2135.6 i-PTSM Score 51 50 69 66 Efficacy Score/ 1.53 1.56 1.34 2.05 StainScore Ratio

EXAMPLE II

Example II illustrates single phase dentifrice compositionsincorporating stannous ion salts, dispersions of suspended Glass Hpolyphosphates or polyphosphonate polymer and various fluoride ionsources all formulated within low water base to facilitate polymeric MSAstability and stannous ion stability. Also shown is an example of astannous-containing dentifrice as described in U.S. Pat. No. 5,004,597to Majeti et al.

Example II compositions (Formula A-D below) are prepared as follows. Addthe glycerin and thickening agents to the main mix tank and mix untilhomogeneous. If applicable, add the sodium gluconate to the main mixtank and mix until homogeneous. Add the sodium lauryl sulfate solutionand flavor to the main mix tank and mix until thickeners arehydrated/dissolved. Add the silica and titanium dioxide to the main mixtank and mix until homogeneous. Add stannous and/or fluoride salts tothe main mix tank and mix until homogeneous. Finally add the polymericsurface active agent (Glass H or polyphosphonate) to the main mix tank.Mix until homogeneous.

The comparative example of a stannous-containing dentifrice is preparedas follows as described in U.S. Pat. No. 5,004,597 to Majeti, et al.Sorbitol and one half of the water are added to the mix tank and heatingto 77° C. initiated. Saccharin, titanium dioxide, and silica may beadded to the mixture during this heating period. Sufficient agitation ismaintained to prevent the settling of the insoluble components. Theglycerin is added to a separate vessel and is also heated to 77° C. Whenboth the solutions have attained the required temperature, thecarboxymethyl cellulose (CMC) is slowly added to the glycerin undervigorous agitation. When the CMC is sufficiently dispersed in theglycerin, this mixture is added to the sorbitol/water mixture. Theresulting mixture is then blended for a period of time sufficient toallow complete hydration of the binders (about 15 minutes). When thepaste is of acceptable texture, the flavor, sodium alkyl sulfate, andcolor are added. One half of the remaining water is then added to aseparate mix tank and allowed to heat to 77° C. After the water attainsthe necessary temperature, the sodium gluconate is added under mediumagitation and allowed to dissolve completely. The stannous chloridedihydrate is then added to the gluconate solution and also allowed todissolve. This mixture is added to the main mix. The stannous fluorideis added to the remaining water (also at 77° C.) and the resultingsolution is added to the main mix and allowed to blend thoroughly beforefinal pH adjustment with sodium hydroxide. The completed paste isagitated for approximately 20 minutes before being milled and deaerated.

Formula Formula Formula Formula Comparative Ingredient A B C D ExampleFlavor 1.000 1.200 1.500 1.150 1.000 Glycerin 53.166 54.300 52.872 9.00014.425 Poloxamer 407 5.000 3.000 8.000 — — Stannous Chloride 0.680 — —1.500 1.500 Stannous Sulfate — 1.460 — — — Stannous Fluoride 0.454 — —0.454 0.454 Sodium Fluoride — 0.320 — — — Sodium — — 1.128 — — Mono-fluorophosphate Sodium Lauryl 7.500 6.000 4.000 4.000 5.000Sulfate^((a)) Silica 20.000 18.000 22.000 22.000 20.000 Carboxymethyl0.200 0.200 0.400 0.350 0.600 Cellulose Sodium Gluconate — 1.470 — —2.100 Sodium Saccharin 0.400 0.350 0.500 0.460 0.300 Titanium Dioxide0.500 0.500 0.500 — 0.525 Xanthan Gum 0.100 0.200 0.100 0.350 0.700Glass H 11.000 13.000 9.000 — — Polyphosphonate 5.000 — Nahydroxide^((b)) — 0.600 FD&C Blue #1^((c)) — 0.300 Sorbitol^((d)) 30.43037.496 Water 25.306 15.000 ^((a))27.9% solution ^((b))50% solution^((c))1% solution ^((d))70% solution

What is claimed is:
 1. An oral composition having antimicrobial activityeffective for reducing plaque and gingivitis, said compositioncomprising: a. a stannous ion source that comprises a stannous saltother than stannous fluoride or stannous monofluorophosphate and iscapable of delivering from about 3,000 ppm to about 15,000 ppm stannousions, b. a fluoride ion source, and c. a polymeric surface active agent,which is a polyelectrolyte selected from the group consisting ofcondensed phosphorylated polymers; polyphosphonates; carboxy-substitutedalcohol polymers; copolymers of phosphonate- or phosphonate-containingmonomers or polymers with ethylenically unsaturated monomers, aminoacids, or with other polymers selected from proteins, polypeptides,polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate),poly(ethacrylate), poly(hydroxyalkylmethacrylate), poly(vinyl alcohol),poly(maleic anhydride), poly(maleate) poly(amide), poly(ethylene amine),poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) orpoly(vinyl benzyl chloride); and mixtures thereof, wherein saidpolymeric surface active agent binds stannous ions.
 2. The oralcomposition according to claim 1 wherein the fluoride ion source iscapable of providing from about 50 ppm to about 3500 ppm of fluorideions.
 3. The oral composition according to claim 1 comprising from about1% to about 35% by weight of the composition of the polymeric surfaceactive agent.
 4. The oral composition according to claim 1 wherein thefluoride ion source comprises stannous fluoride.
 5. The oral compositionaccording to claim 4 wherein the stannous ion source comprises stannouschloride dihydrate.
 6. The oral composition according to claim 5additionally comprising a gluconate salt.
 7. The oral compositionaccording to claim 1 wherein the stannous ion source and fluoride ionsource are physically separated from the polymeric surface active agent.8. The oral composition according to claim 1 wherein the ratio of saidcomposition's in-vitro Plaque Glycolysis Regrowth Model score toin-vitro Pellicle Tea Stain Model score is at least about 1.2.
 9. Theoral composition according to claim 1 wherein the composition's in-vitroPlaque Glycolysis Regrowth Model score is at least about 60%.
 10. Theoral composition according to claim 1 wherein the composition's in-vitroPellicle Tea Stain Model score is less than about 75%.
 11. The oralcomposition according to claim 9 wherein the composition's in-vitroPlaque Glycolysis Regrowth Model score is at least about 70%.
 12. Theoral composition according to claim 9 wherein the composition's in-vitroPlaque Glycolysis Regrowth Model score is at least about 80%.
 13. Theoral composition according to claim 10 wherein the composition'sin-vitro Pellicle Tea Stain Model score is less than about 60%.
 14. Theoral composition according to claim 10 wherein the composition'sin-vitro Pellicle Tea Stain Model score is less than about 50%.
 15. Theoral composition according to claim 10 wherein the composition'sin-vitro Pellicle Tea Stain Model score is less than about 25%.
 16. Theoral composition according to claim 1 wherein the oral composition isfree of alkali metal pyrophosphate salt.
 17. The oral formulationaccording to claim 1 wherein the oral composition additionally comprisesa poloxamer.
 18. A method of reducing tartar, plaque and gingivitis in asubject, comprising administering to said subject's oral cavity acomposition comprising a. a stannous ion source that comprises astannous salt other than stannous fluoride or stannousmonofluorophosphate and is capable of delivering from about 3,000 ppm toabout 15,000 ppm stannous ions, b. a fluoride ion source, and c. apolymeric surface active agent, which is a polyelectrolyte selected fromthe group consisting of polyphosphonates; carboxy-substituted alcoholpolymers; copolymers of phosphonate- or phosphonate-containing monomersor polymers with ethylenically unsaturated monomers, amino acids, orwith other polymers selected from proteins, polypeptides,polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate),poly(ethacrylate), poly(hydroxyalkylmethacrylate), poly(vinyl alcohol),poly(maleic anhydride), poly(maleate) poly(amide), poly(ethylene amine),poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) orpoly(vinyl benzyl chloride); and mixtures thereof, wherein saidpolymeric surface active agent binds stannous ions.